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A novel scaffold to fight Pseudomonas aeruginosa pyocyanin production: early steps to novel antivirulence drugs.

Authors
  • Froes, Thamires Quadros1
  • Guido, Rafael Vc2
  • Metwally, Kamel3
  • Castilho, Marcelo Santos1, 4
  • 1 Programa de Pós-graduação em Biotecnologia da Universidade Estadual de Feira de Santana, Bahia, CEP 44036-900, Brazil. , (Brazil)
  • 2 Instituto de Física de São Carlos, Universidade de São Paulo, São Paulo, CEP 13563-120, Brazil. , (Brazil)
  • 3 Department of Medicinal Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt. , (Egypt)
  • 4 Faculdade de Farmácia da Universidade Federal da Bahia, Bahia, CEP 40170-115, Brazil. , (Brazil)
Type
Published Article
Journal
Future Medicinal Chemistry
Publisher
"Future Science, LTD"
Publication Date
Aug 01, 2020
Volume
12
Issue
16
Pages
1489–1503
Identifiers
DOI: 10.4155/fmc-2019-0351
PMID: 32772556
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Aim: Although bacterial resistance is a growing concern worldwide, the development of antibacterial drugs has been steadily decreasing. One alternative to fight this issue relies on reducing the bacteria virulence without killing it. PhzS plays a pivotal role in pyocyanin production in Pseudomonas aeruginosa. Results: A total of 31 thiazolidinedione derivatives were evaluated as putative PhzS inhibitors, using thermo shift assays. Compounds that significantly shifted PhzS's Tm had their mode of inhibition (cofactor competitor) and affinity calculated by thermo shift assays as well. The most promising compound (E)-5-(4-((4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)methoxy)benzylidene)thiazolidine-2,4-dione had their affinity confirmed by microscale thermophoresis (Kd = 18 μM). Cellular assays suggest this compound reduces pyocyanin production in vitro, but does not affect P. aeruginosa viability. Conclusion: The first inhibitor of PhzS is described.

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